Identification of serological markers of protection and risk for dengue vaccines and natural infection

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Project Summary Dengue remains stubbornly endemic in many countries. Vaccine development efforts have been hampered by a poor understanding of the immune response. We do know that pre-existing immunity from vaccination or historic infections is key to driving disease risk, however, accurate markers of risk or protection are lacking, including how they change over multiple years. Less is known about the role of non-neutralizing antibody functions, such as antibody-dependent cell cytotoxicity, and antibody-dependent enhancement in driving disease risk. Neutralizing and non-neutralizing antibody responses have not been characterized alongside cellular immune responses that have been identified to be associated with risk of illness. Here, we will expand upon previous work on the diversity of neutralization responses to specifically add characterization of non-neutralizing antibody responses and cellular immune responses from natural infection and vaccination using samples taken from the same individuals over numerous time points. These samples come from cohorts that had regular collection of sera and PBMC and were followed for instances of infection and illness, many of which severe. This includes a cohort of individuals that were vaccinated by the only licensed dengue vaccine, a cohort followed for 13 years. We also have access to samples from individuals vaccinated with another candidate vaccine followed over five years. Finally, we will re-recruit cohort participants to provide samples 23 years after their participation to investigate long term responses after infections. We will measure multiple non-neutralizing and neutralizing responses to a diverse set of dengue viruses a wide range of antibody measures as well as a limited set of cellular immune responses, providing a multi-dimensional, systems characterization of humoral and cellular immune responses. We will use this multi-dimensional measure and mathematical models to reconstruct full infection histories and immune dynamics. These efforts will provide a set of correlates of protection/risk of illness and infection that can be used to assess risk in vaccine trials and epidemiological studies. These mechanistic models will be generally useful to infer dynamics of immune responses to antigenically variable pathogens and can be used to assist in the design and analysis of vaccine trials and epidemiological studies. Relevance to Public Health Multiple candidate dengue vaccines are currently in development, however, their likely effectiveness over short and long time periods remain unknown due to a lack of good markers of protection or risk. Identifying such markers, and how they change over time is critical to their optimal use, continued efficacy and population safety. More broadly, characterization of non-neutralizing antibody and cellular immune responses to a diverse set of dengue viruses alongside neutralizing responses in humans followed over many years who have experienced dengue infection and/or vaccination will increase our understanding of immune responses to dengue.